Abstract: The goal of this project is to characterize a potentially treatable factor associated with cognitive impairments in subjects with early onset schizophrenia (EOS). EOS is a relatively less well studied form of severe mental illness with more severe cognitive impairments and poorer long term outcomes compared to the adult onset schizophrenia (AOS). Because of early onset, individuals with EOS suffer from more severe and protracted disability. An important contributing factor to poor long term outcome in schizophrenia is cognitive impairments. Since these cognitive deficits are refractory to currently prescribed antipsychotics, there is an urgent need to examine factors associated with cognitive impairments in SZ. More importantly, the disease onset in EOS occurs during an active phase of neurodevelopment. Therefore, it is logical to examine the patterns of exposure including prenatal exposure that may have a bearing on neurodevelopment associated with cognitive deficits. Human studies including ours suggest that exposure to Herpes Simplex Virus, subtype 1 (HSV1) may be one of them. HSV1 is a double stranded DNA virus that causes common cold sores and requires lodging in the nervous system for its life cycle. In the US, nearly 60% of pregnant mothers and 45% of adolescents (12-19 years) are exposed to this virus. Majority of individuals exposed to HSV1 develop chronic infection and only a minority develop encephalitis. Earlier studies have consistently associated cognitive impairments and reduced grey matter volume in the prefrontal cortex among AOS subjects exposed to HSV1. We observed longitudinal changes in cognitive impairments and grey matter loss in AOS subjects exposed to HSV1. Interestingly, AOS subjects treated with an anti-herpes medication (Valacyclovir) added to an anti- psychotic showed improvement in working memory, verbal memory and visual learning compared to those who received placebo and an antipsychotic. This proposal seeks to examine the association of cognitive impairments, morphometric and membrane chemical abnormalities in subjects with EOS (aim 1) and to explore the patterns of timing of exposure with these phenotypes (aim 2). To accomplish aim 2, we will capitalize on our access to the pregnancy, delivery and neonatal data along with banked blood samples in a set of repositories at the Magee Women's Hospital (MWH). The largest of the databases contains data and blood samples on more than 110,000 mothers. This data is supplemented by prospective ldata and biological samples on more than 3000 mothers collected under different federally funded projects (PI: Dr. Simhan and Dr. Roberts). Drs. Hyagriv Simhan is the director of the MWH repository and PI on his federally funded projects is a co-investigator on this project to facilitate access to the repository. Dr. James Roberts is a consultant on this project who will make them available for this study. Combining the prospective data collection with access to the repository is the most cost effective and rapid approach to characterize timing of exposure to a potentially treatable factor. The latter may pave the way for future studies on potentially preventive strategies. PUBLIC HEALTH RELEVANCE: Public Health Significance Early Onset Schizophrenia (EOS) is a more severely debilitating disorder than the adult onset schizophrenia (AOS) with considerably poorer outcome. This adds to major public health burden of severe mental illness. Since the onset, by definition, occurs early in life, the morbidity due to the illness lasts much longer than the AOS. Currently available treatments minimally affect cognitive impairments. Characterizing potentially treatable factors associated with cognitive impairments may contribute to better outcomes, thus reducing the morbidity. The proposed effort is driven by intriguing data that supports longitudinal changes in cognition and brain morphology and the reversal of longitudinal cognitive changes by anti-herpes medication.